2. Academic Validation
  3. cGAS guards against chromosome end-to-end fusions during mitosis and facilitates replicative senescence

cGAS guards against chromosome end-to-end fusions during mitosis and facilitates replicative senescence

  • Protein Cell. 2022 Jan;13(1):47-64. doi: 10.1007/s13238-021-00879-y.
Xiaocui Li 1,  Xiaojuan Li 1,  Chen Xie 1,  Sihui Cai 1,  Mengqiu Li 1,  Heping Jin 1,  Shu Wu 1,  Jun Cui 1,  Haiying Liu 2 3,  Yong Zhao 1 4
Affiliations

Affiliations

  • 1 MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510006, China.
  • 2 MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510006, China. liuhy5@mail.sysu.edu.cn.
  • 3 Department of Biochemistry, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510006, China. liuhy5@mail.sysu.edu.cn.
  • 4 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510006, China.
PMID: 34676498 DOI: 10.1007/s13238-021-00879-y
Abstract

As a sensor of cytosolic DNA, the role of Cyclic GMP-AMP Synthase (cGAS) in innate immune response is well established, yet how its functions in different biological conditions remain to be elucidated. Here, we identify cGAS as an essential regulator in inhibiting mitotic DNA double-strand break (DSB) repair and protecting short telomeres from end-to-end fusion independent of the canonical cGAS-STING pathway. cGAS associates with telomeric/subtelomeric DNA during mitosis when TRF1/TRF2/POT1 are deficient on telomeres. Depletion of cGAS leads to mitotic chromosome end-to-end fusions predominantly occurring between short telomeres. Mechanistically, cGAS interacts with CDK1 and positions them to chromosome ends. Thus, CDK1 inhibits mitotic non-homologous end joining (NHEJ) by blocking the recruitment of RNF8. cGAS-deficient human primary cells are defective in entering replicative senescence and display chromosome end-to-end fusions, genome instability and prolonged growth arrest. Altogether, cGAS safeguards genome stability by controlling mitotic DSB repair to inhibit mitotic chromosome end-to-end fusions, thus facilitating replicative senescence.

Keywords

DNA damage response; cGAS; chromosome end-to-end fusion; genome stability; mitosis; non-homologous end joining; telomeres.

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